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1.
Cell ; 185(22): 4206-4215.e11, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36206754

RESUMO

Mucus protects the epithelial cells of the digestive and respiratory tracts from pathogens and other hazards. Progress in determining the molecular mechanisms of mucus barrier function has been limited by the lack of high-resolution structural information on mucins, the giant, secreted, gel-forming glycoproteins that are the major constituents of mucus. Here, we report how mucin structures we determined enabled the discovery of an unanticipated protective role of mucus: managing the toxic transition metal copper. Using two juxtaposed copper binding sites, one for Cu2+ and the other for Cu1+, the intestinal mucin, MUC2, prevents copper toxicity by blocking futile redox cycling and the squandering of dietary antioxidants, while nevertheless permitting uptake of this important trace metal into cells. These findings emphasize the value of molecular structure in advancing mucosal biology, while introducing mucins, produced in massive quantities to guard extensive mucosal surfaces, as extracellular copper chaperones.


Assuntos
Cobre , Mucinas , Mucinas/metabolismo , Mucina-2 , Cobre/análise , Cobre/metabolismo , Intestinos , Muco/metabolismo , Mucosa Intestinal/metabolismo
2.
Cell ; 185(20): 3705-3719.e14, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36179667

RESUMO

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteroides , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Meropeném , Camundongos , Mucinas/metabolismo , Muco/metabolismo , Polissacarídeos/metabolismo , Xilose
3.
Annu Rev Biochem ; 90: 605-630, 2021 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-33503381

RESUMO

The functions of coat protein complex II (COPII) coats in cargo packaging and the creation of vesicles at the endoplasmic reticulum are conserved in eukaryotic protein secretion. Standard COPII vesicles, however, cannot handle the secretion of metazoan-specific cargoes such as procollagens, apolipoproteins, and mucins. Metazoans have thus evolved modules centered on proteins like TANGO1 (transport and Golgi organization 1) to engage COPII coats and early secretory pathway membranes to engineer a novel mode of cargo export at the endoplasmic reticulum.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas/metabolismo , Animais , Apolipoproteínas/metabolismo , Translocador Nuclear Receptor Aril Hidrocarboneto/química , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Colágeno/metabolismo , Evolução Molecular , Humanos , Mucinas/metabolismo , Família Multigênica , Transporte Proteico , Proteínas/química
4.
Annu Rev Biochem ; 89: 769-793, 2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32243763

RESUMO

Generating the barriers that protect our inner surfaces from bacteria and other challenges requires large glycoproteins called mucins. These come in two types, gel-forming and transmembrane, all characterized by large, highly O-glycosylated mucin domains that are diversely decorated by Golgi glycosyltransferases to become extended rodlike structures. The general functions of mucins on internal epithelial surfaces are to wash away microorganisms and, even more importantly, to build protective barriers. The latter function is most evident in the large intestine, where the inner mucus layer separates the numerous commensal bacteria from the epithelial cells. The host's conversion of MUC2 to the outer mucus layer allows bacteria to degrade the mucin glycans and recover the energy content that is then shared with the host. The molecular nature of the mucins is complex, and how they construct the extracellular complex glycocalyx and mucus is poorly understood and a future biochemical challenge.


Assuntos
Microbioma Gastrointestinal/fisiologia , Glicocálix/química , Glicosiltransferases/química , Células Caliciformes/química , Mucinas/química , Muco/química , Animais , Configuração de Carboidratos , Sequência de Carboidratos , Expressão Gênica , Glicocálix/metabolismo , Glicosilação , Glicosiltransferases/classificação , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Células Caliciformes/metabolismo , Células Caliciformes/microbiologia , Humanos , Mucinas/classificação , Mucinas/genética , Mucinas/metabolismo , Muco/metabolismo , Muco/microbiologia , Simbiose/fisiologia
5.
Cell ; 183(3): 717-729.e16, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33031746

RESUMO

The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.


Assuntos
Biopolímeros/metabolismo , Mucinas/metabolismo , Fator de von Willebrand/metabolismo , Sequência de Aminoácidos , Animais , Microscopia Crioeletrônica , Dissulfetos/metabolismo , Feminino , Glicosilação , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mucinas/química , Mucinas/ultraestrutura , Peptídeos/química , Domínios Proteicos , Multimerização Proteica , Fator de von Willebrand/química , Fator de von Willebrand/ultraestrutura
6.
Cell ; 177(7): 1757-1770.e21, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31056282

RESUMO

Cells bend their plasma membranes into highly curved forms to interact with the local environment, but how shape generation is regulated is not fully resolved. Here, we report a synergy between shape-generating processes in the cell interior and the external organization and composition of the cell-surface glycocalyx. Mucin biopolymers and long-chain polysaccharides within the glycocalyx can generate entropic forces that favor or disfavor the projection of spherical and finger-like extensions from the cell surface. A polymer brush model of the glycocalyx successfully predicts the effects of polymer size and cell-surface density on membrane morphologies. Specific glycocalyx compositions can also induce plasma membrane instabilities to generate more exotic undulating and pearled membrane structures and drive secretion of extracellular vesicles. Together, our results suggest a fundamental role for the glycocalyx in regulating curved membrane features that serve in communication between cells and with the extracellular matrix.


Assuntos
Forma Celular , Matriz Extracelular/metabolismo , Glicocálix/metabolismo , Glicoproteínas de Membrana/metabolismo , Mucinas/metabolismo , Animais , Linhagem Celular , Matriz Extracelular/genética , Glicocálix/genética , Cavalos , Humanos , Glicoproteínas de Membrana/genética , Mucinas/genética
7.
Immunity ; 55(5): 895-911.e10, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35483356

RESUMO

Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response-a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This "niche remodeling" by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.


Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Proteínas de Bactérias , Humanos , Inflamação , Mucinas
8.
Cell ; 160(5): 904-912, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25723165

RESUMO

The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 Å crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry.


Assuntos
Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Marburgvirus/química , Proteínas do Envelope Viral/química , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Complexo Antígeno-Anticorpo/química , Linhagem Celular , Reações Cruzadas , Cristalografia por Raios X , Drosophila , Ebolavirus/química , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/metabolismo , Doença do Vírus de Marburg/imunologia , Marburgvirus/genética , Marburgvirus/imunologia , Modelos Moleculares , Dados de Sequência Molecular , Mucinas/química , Alinhamento de Sequência , Proteínas do Envelope Viral/metabolismo
9.
EMBO J ; 43(5): 695-718, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38177501

RESUMO

Intestinal goblet cells are secretory cells specialized in the production of mucins, and as such are challenged by the need for efficient protein folding. Goblet cells express Inositol-Requiring Enzyme-1ß (IRE1ß), a unique sensor in the unfolded protein response (UPR), which is part of an adaptive mechanism that regulates the demands of mucin production and secretion. However, how IRE1ß activity is tuned to mucus folding load remains unknown. We identified the disulfide isomerase and mucin chaperone AGR2 as a goblet cell-specific protein that crucially regulates IRE1ß-, but not IRE1α-mediated signaling. AGR2 binding to IRE1ß disrupts IRE1ß oligomerization, thereby blocking its downstream endonuclease activity. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1ß activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum set the threshold for IRE1ß activation. We found that AGR2 mutants lacking their catalytic cysteine, or displaying the disease-associated mutation H117Y, were no longer able to dampen IRE1ß activity. Collectively, these results demonstrate that AGR2 is a central chaperone regulating the goblet cell UPR by acting as a rheostat of IRE1ß endonuclease activity.


Assuntos
Células Caliciformes , Chaperonas Moleculares , Mucinas , Endonucleases , Células Caliciformes/metabolismo , Chaperonas Moleculares/genética , Mucinas/genética , Isomerases de Dissulfetos de Proteínas , Humanos , Linhagem Celular Tumoral
10.
EMBO J ; 43(5): 719-753, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38177498

RESUMO

Effector mechanisms of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) are well-characterised, but how ER proteostasis is sensed is less well understood. Here, we exploited the beta isoform of the UPR transducer IRE1, that is specific to mucin-producing cells in order to gauge the relative regulatory roles of activating ligands and repressing chaperones of the specialised ER of goblet cells. Replacement of the stress-sensing luminal domain of endogenous IRE1α in CHO cells (normally expressing neither mucin nor IRE1ß) with the luminal domain of IRE1ß deregulated basal IRE1 activity. The mucin-specific chaperone AGR2 repressed IRE1 activity in cells expressing the domain-swapped IRE1ß/α chimera, but had no effect on IRE1α. Introduction of the goblet cell-specific client MUC2 reversed AGR2-mediated repression of the IRE1ß/α chimera. In vitro, AGR2 actively de-stabilised the IRE1ß luminal domain dimer and formed a reversible complex with the inactive monomer. These features of the IRE1ß-AGR2 couple suggest that active repression of IRE1ß by a specialised mucin chaperone subordinates IRE1 activity to a proteostatic challenge unique to goblet cells, a challenge that is otherwise poorly recognised by the pervasive UPR transducers.


Assuntos
Endorribonucleases , Células Caliciformes , Mucinas , Animais , Cricetinae , Humanos , Cricetulus , Células Caliciformes/metabolismo , Chaperonas Moleculares/genética , Mucinas/genética , Mucoproteínas/genética , Proteínas Oncogênicas , Proteínas Serina-Treonina Quinases/genética , Células CHO
11.
Nature ; 603(7903): 949-956, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35322233

RESUMO

Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes1-4. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex5, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion6. Disruption of Ca2+-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis7-11. Here we designed a hydrocarbon-stapled peptide that specifically disrupts Ca2+-triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and the Ca2+-binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMP8, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca2+-triggered fusion at physiological Ca2+ concentrations. Conjugation of cell-penetrating peptides to the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca2+-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.


Assuntos
Cálcio , Hidrocarbonetos , Fusão de Membrana , Mucinas , Proteínas SNARE , Animais , Cálcio/metabolismo , Hidrocarbonetos/química , Fusão de Membrana/fisiologia , Camundongos , Mucinas/metabolismo , Neurotransmissores/metabolismo , Peptídeos/farmacologia , Mucosa Respiratória , Proteínas SNARE/metabolismo
12.
Nature ; 610(7931): 349-355, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36171290

RESUMO

Entomopathogenic nematodes are widely used as biopesticides1,2. Their insecticidal activity depends on symbiotic bacteria such as Photorhabdus luminescens, which produces toxin complex (Tc) toxins as major virulence factors3-6. No protein receptors are known for any Tc toxins, which limits our understanding of their specificity and pathogenesis. Here we use genome-wide CRISPR-Cas9-mediated knockout screening in Drosophila melanogaster S2R+ cells and identify Visgun (Vsg) as a receptor for an archetypal P. luminescens Tc toxin (pTc). The toxin recognizes the extracellular O-glycosylated mucin-like domain of Vsg that contains high-density repeats of proline, threonine and serine (HD-PTS). Vsg orthologues in mosquitoes and beetles contain HD-PTS and can function as pTc receptors, whereas orthologues without HD-PTS, such as moth and human versions, are not pTc receptors. Vsg is expressed in immune cells, including haemocytes and fat body cells. Haemocytes from Vsg knockout Drosophila are resistant to pTc and maintain phagocytosis in the presence of pTc, and their sensitivity to pTc is restored through the transgenic expression of mosquito Vsg. Last, Vsg knockout Drosophila show reduced bacterial loads and lethality from P. luminescens infection. Our findings identify a proteinaceous Tc toxin receptor, reveal how Tc toxins contribute to P. luminescens pathogenesis, and establish a genome-wide CRISPR screening approach for investigating insecticidal toxins and pathogens.


Assuntos
Toxinas Bacterianas , Sistemas CRISPR-Cas , Proteínas de Drosophila , Drosophila melanogaster , Edição de Genes , Fatores de Virulência , Animais , Toxinas Bacterianas/metabolismo , Agentes de Controle Biológico , Culicidae , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/microbiologia , Corpo Adiposo/citologia , Técnicas de Silenciamento de Genes , Hemócitos , Humanos , Mariposas , Mucinas , Controle Biológico de Vetores , Fagocitose , Photorhabdus/metabolismo , Sequências Repetitivas de Aminoácidos , Transgenes , Fatores de Virulência/metabolismo
13.
EMBO J ; 42(2): e113013, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36382686

RESUMO

Intestinal mucin glycosylation is important for mucus-bacterial homeostasis and is altered in disease. In this issue of The EMBO Journal, Ilani et al (2022) identify the Golgi enzyme quiescin sulfhydryl oxidase 1 (QSOX1) as a novel mucus regulator by controlling mucin sialylation.


Assuntos
Intestinos , Mucinas , Glicosilação , Oxigênio
14.
EMBO J ; 42(3): e111562, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36504455

RESUMO

Pandemic and endemic strains of Vibrio cholerae arise from toxigenic conversion by the CTXφ bacteriophage, a process by which CTXφ infects nontoxigenic strains of V. cholerae. CTXφ encodes the cholera toxin, an enterotoxin responsible for the watery diarrhea associated with cholera infections. Despite the critical role of CTXφ during infections, signals that affect CTXφ-driven toxigenic conversion or expression of the CTXφ-encoded cholera toxin remain poorly characterized, particularly in the context of the gut mucosa. Here, we identify mucin polymers as potent regulators of CTXφ-driven pathogenicity in V. cholerae. Our results indicate that mucin-associated O-glycans block toxigenic conversion by CTXφ and suppress the expression of CTXφ-related virulence factors, including the toxin co-regulated pilus and cholera toxin, by interfering with the TcpP/ToxR/ToxT virulence pathway. By synthesizing individual mucin glycan structures de novo, we identify the Core 2 motif as the critical structure governing this virulence attenuation. Overall, our results highlight a novel mechanism by which mucins and their associated O-glycan structures affect CTXφ-mediated evolution and pathogenicity of V. cholerae, underscoring the potential regulatory power housed within mucus.


Assuntos
Bacteriófagos , Toxina da Cólera , Mucinas , Vibrio cholerae , Virulência , Bacteriófagos/genética , Bacteriófagos/patogenicidade , Toxina da Cólera/genética , Toxina da Cólera/metabolismo , Mucinas/genética , Mucinas/metabolismo , Vibrio cholerae/genética , Vibrio cholerae/metabolismo , Virulência/genética , Virulência/fisiologia , Polissacarídeos/genética , Polissacarídeos/metabolismo
15.
EMBO J ; 42(3): e113204, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36573348

RESUMO

Vibrio cholerae, the causative agent of cholera, must first be converted to its toxigenic form and cross the sugar-rich mucus barrier before it can cause disease, but whether these hurdles are linked is unclear. In this issue, Wang et al (2022) provide new evidence that mucus O-glycans directly prevent toxigenic conversion and virulence factor expression in V. cholerae.


Assuntos
Toxina da Cólera , Cólera , Mucinas , Vibrio cholerae , Fatores de Virulência , Humanos , Cólera/metabolismo , Cólera/microbiologia , Toxina da Cólera/metabolismo , Mucinas/metabolismo , Vibrio cholerae/metabolismo , Vibrio cholerae/patogenicidade , Fatores de Virulência/metabolismo , Polissacarídeos/metabolismo
16.
EMBO J ; 42(2): e111869, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36245281

RESUMO

Mucus is made of enormous mucin glycoproteins that polymerize by disulfide crosslinking in the Golgi apparatus. QSOX1 is a catalyst of disulfide bond formation localized to the Golgi. Both QSOX1 and mucins are highly expressed in goblet cells of mucosal tissues, leading to the hypothesis that QSOX1 catalyzes disulfide-mediated mucin polymerization. We found that knockout mice lacking QSOX1 had impaired mucus barrier function due to production of defective mucus. However, an investigation on the molecular level revealed normal disulfide-mediated polymerization of mucins and related glycoproteins. Instead, we detected a drastic decrease in sialic acid in the gut mucus glycome of the QSOX1 knockout mice, leading to the discovery that QSOX1 forms regulatory disulfides in Golgi glycosyltransferases. Sialylation defects in the colon are known to cause colitis in humans. Here we show that QSOX1 redox control of sialylation is essential for maintaining mucosal function.


Assuntos
Glicosiltransferases , Complexo de Golgi , Mucosa Intestinal , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Animais , Camundongos , Colo/metabolismo , Dissulfetos/metabolismo , Glicoproteínas , Glicosiltransferases/metabolismo , Complexo de Golgi/metabolismo , Mucinas/química , Mucinas/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Mucosa Intestinal/metabolismo
17.
Nat Immunol ; 16(1): 27-35, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25521682

RESUMO

The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host-defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and 'instruct' the professional immune system to protect the lungs from infection and injury.


Assuntos
Imunidade Inata/imunologia , Pulmão/imunologia , Mucosa Respiratória/imunologia , Animais , Homeostase/imunologia , Humanos , Pulmão/citologia , Mucinas/imunologia , Mucosa Respiratória/citologia , Transdução de Sinais/imunologia
18.
Nature ; 598(7880): 332-337, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34616040

RESUMO

Humans have co-evolved with a dense community of microbial symbionts that inhabit the lower intestine. In the colon, secreted mucus creates a barrier that separates these microorganisms from the intestinal epithelium1. Some gut bacteria are able to utilize mucin glycoproteins, the main mucus component, as a nutrient source. However, it remains unclear which bacterial enzymes initiate degradation of the complex O-glycans found in mucins. In the distal colon, these glycans are heavily sulfated, but specific sulfatases that are active on colonic mucins have not been identified. Here we show that sulfatases are essential to the utilization of distal colonic mucin O-glycans by the human gut symbiont Bacteroides thetaiotaomicron. We characterized the activity of 12 different sulfatases produced by this species, showing that they are collectively active on all known sulfate linkages in O-glycans. Crystal structures of three enzymes provide mechanistic insight into the molecular basis of substrate specificity. Unexpectedly, we found that a single sulfatase is essential for utilization of sulfated O-glycans in vitro and also has a major role in vivo. Our results provide insight into the mechanisms of mucin degradation by a prominent group of gut bacteria, an important process for both normal microbial gut colonization2 and diseases such as inflammatory bowel disease3.


Assuntos
Bacteroides/enzimologia , Colo/metabolismo , Colo/microbiologia , Microbioma Gastrointestinal , Mucinas/metabolismo , Sulfatases/metabolismo , Acetilgalactosamina/química , Acetilgalactosamina/metabolismo , Animais , Colo/química , Cristalografia por Raios X , Feminino , Galactose/metabolismo , Humanos , Masculino , Camundongos , Modelos Moleculares , Especificidade por Substrato , Sulfatases/química
19.
Semin Immunol ; 69: 101807, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37478802

RESUMO

A complex mucus network made up of large polymers of the mucin-family glycoprotein MUC2 exists between the large intestinal microbial mass and epithelial and immune cells. This has long been understood as an innate immune defense barrier against the microbiota and other luminal threats that reinforces the barrier function of the epithelium and limits microbiota contact with the tissues. However, past and recent studies have provided new evidence of how critical the mucus network is to act as a 'liaison' between host and microbe to mediate anti-inflammatory, mutualistic interactions with the microbiota and protection from pathogens. This review summarizes historical and recent insights into the formation of the gut mucus network, how the microbes and immune system influence mucus, and in turn, how the mucus influences immune responses to the microbiota.


Assuntos
Mucosa Intestinal , Microbiota , Humanos , Mucina-2 , Muco , Mucinas
20.
Proc Natl Acad Sci U S A ; 121(6): e2314309121, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38285943

RESUMO

Mucins are large, highly glycosylated extracellular matrix proteins that line and protect epithelia of the respiratory, digestive, and urogenital tracts. Previous work has shown that mucins form large, interconnected polymeric networks that mediate their biological functions once secreted. However, how these large matrix molecules are compacted and packaged into much smaller secretory granules within cells prior to secretion is largely unknown. Here, we demonstrate that a small cysteine-rich adaptor protein is essential for proper packaging of a secretory mucin in vivo. This adaptor acts via cysteine bonding between itself and the cysteine-rich domain of the mucin. Loss of this adaptor protein disrupts mucin packaging in secretory granules, alters the mobile fraction within granules, and results in granules that are larger, more circular, and more fragile. Understanding the factors and mechanisms by which mucins and other highly glycosylated matrix proteins are properly packaged and secreted may provide insight into diseases characterized by aberrant mucin secretion.


Assuntos
Cisteína , Mucinas , Mucinas/metabolismo , Cisteína/metabolismo , Transporte Biológico , Vesículas Secretórias/metabolismo
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